Ibuprofen is a well-known non-steroidal, anti-inflammatory (NSAID) drug having analgesic properties. It is mostly administered orally but can be administered topically as well. Ibuprofen has been marketed in the form of a cream in various foreign countries, e.g., as "Dolgit" in Germany and "Brufen" in Portugal. These ibuprofen creams are to be applied topically so that the ibuprofen is delivered in a percutaneous manner through the skin for its effect beneath the skin. The ibuprofen cream is, however, a poor delivery system, and the amount of ibuprofen actually penetrating the skin is very small.
U.S. Pat. No. 4,185,100 entitled "Topical Anti-Inflammatory Drug Therapy" describes a method of topical treatment of an inflammatory condition of the skin comprising applying to the affected area a non-steroidal anti-inflammatory agent and concurrently a topically active anti-inflammatory cortico-steroid, which are applied in a Pharmaceutically-acceptable topical vehicle selected from the group consisting of creams, gels, ointments, powders, aerosols and solutions suitable for topical administration. This patent does not indicate that one vehicle is more effective than any other vehicle.
Kyuki et al., "Anti-Inflammatory Effect of Diclofenac-Sodium Ointment (Cream) in Topical Application", Japan J. Pharmacol. 33, 121-132 (1983) describes the anti-inflammatory effect of a diclofenac-sodium. Ointments were prepared with three kinds of bases: lipophilic, emulsion (cream) and gel bases and their anti-inflammatory effects were compared. The cream base was reported by Kyaki et al. to have the most potent effect.
European Patent Application 0151953 to Beecham Group filed Jan. 17, 1985, published June 21, 1985 entitled "Topical Drug Release System" describes at page 10-11 an ibuprofen CARBOPOL gel system containing ibuprofen, propylene glycol, water, CARBOPOL 940 (polyacrylic acid polymer) and diisopropanolamine, as an illustrative example of a pharmaceutical composition for percutaneous absorption by topical application made in two liquid drug-containing phases, which are to be mixed together in situ just before use to form a supersaturated drug-containing gel. The EPO application discloses a non-alcoholic gel system for delivering ibuprofen topically. It has been unexpectedly found that the hydroalcoholic ibuprofen gels of the present invention at pH of 3.5 to 6.0 are more effective for delivering ibuprofen through the skin of a mammal than either the non-alcoholic ibuprofen gels as disclosed in Beecham's European patent application or the higher pH gels of Kishi et al.
U.S. Pat. No. 4,533,546 entitled "Anti-Inflammatory Analgesic Gelled Ointments" to Kishi et al. discloses NSAID, e.g. ibuprofen, containing hydroalcoholic gels having a pH in the range of 7.0 to 9.0. The gel ointment comprises a phenylacetic acid anti-inflammatory compound, a carboxyvinyl polymer, a water-soluble organic amine, e.g. triethanolamine and water wherein the amount of organic amine is such that the gel ointment has a pH in the range of 7.0 to 9.0 and preferably 7.3 to 7.8.
Ibuprofen (+)2-(p-isobutylphenyl)propionic acid is a racemic mixture of "S" and "R" enantiomer. It has been recognized in the art that the "S" form is the active component of ibuprofen in vitro but that in vivo the racemic mixture is believed to be of substantially equivalent potency because of the metabolic conversion of "R" to "S" by the body. See e.g. Adams et al., Current Medical Research and Opinion, "The Optical Isomers of Ibuprofen", Vol. 3, No. 8 Pg. 552 (1975) and J. Pharm. Pharmac., "Pharmacological Differences Between the Optical Isomer of Ibuprofen: Evidence for Metabolic Conversion of the (-) Isomer", Vol. 28, Pg. 256 (1976); Lee et al., Br. J. Clin. Pharmac., "Stereoselective Disposition of Ibuprofen Enantiomers in Man" Vol. 19, Pg. 669-674 (1985); and Williams et al., 1985 Birkhauser Verlay, Basel "Stereoselective Disposition Basis for Variability in Response to NSAID's" Pp. 119-126. The present inventors find, however, that the topical application of the substantially pure S-enantiomer of ibuprofen applied topically will provide greater analgesic and anti-inflammatory activity to the therapeutic site by not depending on metabolic conversion of the inactive R-enantiomer.